1. Field of the Invention
The present invention relates generally to the fields of pharmacology and medicine and more particularly, it concerns the treatment and prevention of fever, pain and inflammation with non-steroidal anti-inflammatory drugs (NSAIDs) complexed with phospholipids, and in other embodiments in further combination with neutral lipids. The invention also provides methods for retarding platelet aggregation, and the application of these methods in treating cardiovascular and vascular diseases as it relates to platelet activity.
2. Description of the Related Art
The consumption of NSAIDs among the general populace is unparalleled by any other drug class due to their great efficacy in the treatment of pain, inflammation and fever (Rainsford, 1985). The widespread usage of these drugs is anticipated to increase even further due to their efficacy in the treatment of osteoarthritic and generalized aches and pain as the elderly increase as a percentage of the population (Alexander et al., 1985; Jolobe and Montgomery, 1984), and as NSAIDs are employed in the treatment/prevention of stroke and cardiovascular disease.
The major concern with these developments relates to the tendency of NSAIDs to induce gastrointestinal (GI) mucosal lesions, perforations and bleeding resulting in significant morbidity and mortality, even in occasional NSAID users (Rainsford, 1989; Graham, 1989; Allison et al., 1992). Strategies to reduce the gastroduodenal injurious effects of these drugs with enteric coatings, have had limited success due to the delayed therapeutic actions of these specially packaged NSAIDs (Alpsten et al., 1982; Mojaverian et al., 1987).
Although it is clear that the GI side-effects of NSAIDs are in part attributable to their ability to inhibit the biosynthesis of gastroprotective prostaglandins, a significant amount of evidence exists that NSAIDs act locally on the mucosa to induce GI ulcers and bleeding by a prostaglandin-independent mechanism (Rainsford, 1989; Whittle et al., 1980; Whittle, 1981; Ligumsky et al., 1982; McCormack and Brune, 1987).
The present inventor and others have obtained evidence that the mucosa of the stomach and other regions of the GI tract have hydrophobic, non-wettable properties, that protect the underlying epithelium from gastric acid and other luminal toxins (Hills et al, 1983; Goddard et al., 1987; Goddard et al., 1990; Kao et al., 1990). This biophysical characteristic, which can be quantified by contact angle analysis, appears to be attributable to the presence of an extracellular lining of surfactant-like phospholipid on the luminal aspects of the mucus gel layer (Goddard et al., 1990; Kao et al., 1990). Evidence has also come forth that these zwitterionic phospholipids are synthesized in surface mucus cells of the stomach, as well as those present in discrete submucosal glands of the GI tract, where they are stored in specific organelles and secreted by a prostaglandin-dependent pathway (Kao and Lichtenberger, 1991). It has also been reported that aspirin and other NSAIDs have the ability to rapidly transform the gastric mucosa from a non-wettable to a wettable state within minutes after luminal administration, thereby increasing the tissue's susceptibility to the corrosive actions of gastric acid (Hills et al., 1983; Goddard et al., 1987; Goddard et al., 1990; Kao et al., 1990).
One solution to this problem has been to formulate injectable solutions of NSAIDs and thus bypass the GI tract completely. The low water solubility of these drugs, however, has caused problems with this technique. Stable, injectable solutions of indoleacetic and indanacetic acid derivatives have been developed to address this problem, by complexing these NSAIDs with phosphatidylcholine and phosphatidylethanolamine derivatives (See U.S. Pat. No. 4,309,420).
U.S. Pat. No. 4,421,747 describes NSAIDs complexed with phospholipids for oral administration. These complexes were shown to retain their antiinflammatory action and to have reduced ulcer formation in rats. However, no enhancement of therapeutic effects was reported with these preparations.
WO 91/16920 (Vical Inc.) relates to phospholipid prodrug derivatives of a salicylate or non-steroidal, anti-inflammatory drug. These preparations are made by combining salicylic acid or NSAID with a phospholipid in the presence of a coupling agent, thereby producing a covalently linked NSAID-phospholipid compound. These prodrugs are described as useful in reducing the toxicity of high dose, long term usage of NSAID preparations.
JP 3176425 (Nippon Shinyaku KK) relates to compositions including non-steroidal, anti-inflammatory drugs together with neutral lipids and phospholipids in a fat and oil emulsion. Although the method of preparation is not described in the abstract, these compositions appear to be encapsulated in lipid, such as in a micelle. The combination of the drug with the neutral lipids and the phospholipids is described as not affecting the drug's pharmacological actions.
JP 63048228 (Toa Eiyo KK) relates to topically applied compositions that include non-steroidal anti-inflammatory drug together with phospholipid and a "disintegrator". The disintegrator is described as providing for a preparation with improved dispersability and increased absorptivity. JP 63048226 (Ono Pharmaceutical KK) relates to compositions that include a phospholipid base (such as phosphatidylcholine) and an anti-inflammatory agent (such as acetylsalicylic acid and indomethacin). KK JP 58150508 (Ono Pharmaceutical) relates to topical compositions that include a phospholipid base (such as phosphatidylcholine) and an anti-inflammatory agent (such as acetylsalicylic acid and indomethacin).
U.S. Pat. No. 4,369,182 (Nattermann & CIE), relates to inflammation-preventing pharmaceutical compositions for oral administration. The compositions are prepared and then lyophilized into powder form. The described compositions include natural and synthetic phospholipids (dipalmitoylphosphatidylcholine (DPPC)), in combination with nonsteroidal agents including salicylic acid, acetyl-salicylic acid, diflunisal, indomethacin, glucametacine, acemetacin, sulindac, ibuprofen, naproxen, tolmetin and other NSAID's. Also described are NSAID's in combination with phosphatidylcholine preparations, named phospholipons. U.S. Pat. No. 4,421,747 relates to methods of alleviating inflammation with compositions as described in the '182 patent.
Despite the extensive work in the area of NSAIDs, a need continues to exist in the art for preparations that include reduced amounts of this useful class of drug without loss of therapeutic efficacy. Methods and compositions that provide for similar or enhanced anti-pyretic, anti-inflammatory, anti-platelet and analgesic activity at lower doses than currently prescribed for pharmacological activity would also render this very valuable class of drugs available to those previously unable to tolerate standard and/or prolonged therapeutic regimens of NSAID.